The tumor suppressor Rb is a nuclear-phosphoprotein that controls cell proliferation, survival and differentiation and is thought to be either mutated or functionally inactivated by phosphorylation in virtually all human cancer including breast cancer. We developed transgenic mouse models to study the outcomes of upregulating the Rb pathway in the mammary gland and test whether Rb is a universal tumor suppressor. Unphosphorylatable alleles of Rb (RbDeltap34 and RbDeltaKl 1, with 8 and 11 CDK sites mutated) were targeted to the mammary epithelium under control of the MMTV-LTR (proliferating and differentiating mammary epithelium) and WAP (differentiating epithelial cells) promoters. Pre-pubertal MMTV-RbDeltap34 and MMTV-RbDeltaKl 1 transgenic female mice exhibited suppression of ductal growth and branching. During estrus, these transgenic females displayed enlargement of the alveolar compartment. Intriguingly, some MMTV-RbDeltap34 and MMTV- RbDeltaKl 1 transgenic females developed focal hyperplasia as well as full-blown mammary adenocarcinomas. In accord with the more restricted pattern of expression, WAP-RbDeltaKl 1 transgenic mice did not exhibit the early suppression of ductal growth, seen in MMTV-RbDeltaK females, but about 20% developed focal hyperplasia and some developed breast tumors by one year. Though exactly the opposite of what we expect, these provocative and novel results are in accord with our emerging understanding of Rb as a major regulator of both cell proliferation and survival. To determined synergistic or suppressing effects on breast cancer, genetic crosses outlined in the Statement of Work will be carried out by breeding the RbDeltaK transgenic mice with MMTV- Neu and MMTV- wnt mice that are predisosed to breast cancer.

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